Descending bulbospinal pathways originating in n.r. magnocellularis (Nmc) and n. raphe magnus (Nrm) have been implicated in pain modulation and narcotic analgesia. Recent immunohistochemical, iontophoretic and behavioral studies indicate that descending Nmc/Nrm analgesia pathways may involve the interaction of peptide and monoamine neurotransmitter-modulators, particularly substance P (SP), 5-hydroxytryptamine (5-HT) and noradrenaline (NA). The localization of subgroups of these transmitters through Nmc/Nrm suggests a higher degree of organization than has been appreciated, however the fiber trajectory and terminal fields of these subgroups remain unknown. The proposed microiontophoretic autoradiographic experiments will examine these pathways. Two modes of Nmc/Nrm peptide-monoamine interaction have been suggested, both potentially playing important roles in pain modulation. First, some Nmc/Nrm bulbospinal neurons employ two transmitters which are released simultaneously. SP and 5-HT coexist in the same Nme/Nrm neuron, and are transported to the spinal cord where they also coexist in the smae dense core storage vesicles. Although several anatomical experiments have demonstrated the existence of this SP/5-HT system, no studies have as yet examined its functional role in controlling spinal nociceptive unit activity. The proposed microiontophoretic recording studies will be the first to examine the role of the bulbospinal SP/5-HT system in the modulation of pain transmission. Second, other Nmc/Nrm bulbospinal neurons appear to employ only one transmitter per neuron, but two different transmitter systems, acting synergistically, control the same spinal nociceptive unit. Recent electrophysiological experiments suggest that SP, 5-HT and NA act synergistically to modulate each others effect on spinal unit activity, although little data is available on SP, 5-HT and NA synergy in relation to spinal pain transmission. The proposed micriontophoretic recording studies will be the first to examine the synergistic relationship between Nmc/Nrm SP, 5-HT and NA pathways in the modulation of spinal pain transmission.